rs138111911

chr11-124891383-C-Achr11-124891383-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5

The NM_019055.6(ROBO4):c.1864G>T(p.Asp622Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D622H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ROBO4 NM_019055.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22

Genes affected

ROBO4 (HGNC:17985): (roundabout guidance receptor 4) Predicted to enable cell-cell adhesion mediator activity. Involved in angiogenesis and establishment of endothelial barrier. Located in extracellular exosome. Implicated in aortic valve disease 3. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-124891383-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 560401.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO4	NM_019055.6	c.1864G>T	p.Asp622Tyr	missense_variant	12/18	ENST00000306534.8
ROBO4	NM_001301088.2	c.1429G>T	p.Asp477Tyr	missense_variant	12/18
ROBO4	XM_006718861.3	c.1864G>T	p.Asp622Tyr	missense_variant	12/18
ROBO4	XM_011542875.2	c.538G>T	p.Asp180Tyr	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO4	ENST00000306534.8	c.1864G>T	p.Asp622Tyr	missense_variant	12/18	1	NM_019055.6	P1
	ENST00000524433.1	n.80C>A		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000471 AC: 1 AN: 212208 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 112314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1412692 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 696722

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.68
MutPred		0.22		Gain of MoRF binding (P = 0.0344);.;
MVP		0.85
MPC		0.49
ClinPred		0.83	D
GERP RS		5.9
Varity_R		0.30
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138111911; hg19: chr11-124761279;